This postdoctoral F32 Kirschstein NRSA proposes a comprehensive research and training plan in the study of neurogenesis and axon guidance in the olfactory system with relevance to neural regeneration therapies. Failure of the damaged nervous system to repair itself has debilitating consequences for millions of people worldwide. Regeneration therapies are focused on restoring damaged circuitry by regrowth and guidance of the axons of spared neurons or replacement of dead neurons. The olfactory system provides a useful model to study cell replacement and axon targeting in a mature nervous system. Although the mechanisms by which olfactory sensory neuron (OSN) axons are targeted to the olfactory bulb remain largely unknown, the anterior-posterior patterning of glomerular convergence in the bulb correlates with neuronal levels of cAMP and altered expression of activity-dependent guidance cues. However, direct evidence of the involvement of cAMP in axon targeting and the genetic mechanisms involved are lacking. The specific aims of this proposal will test the hypothesis that cAMP plays a definitive role in glomerular convergence of axons in the bulb. If this idea is correct, then transgenic mice exhibiting sustained increases in cAMP in immature OSNs should show altered glomerular convergence and position. Aim 1 will use transgenic mice that express a constitutively active G-protein-coupled receptor, GPR12, in immature OSNs. GPR12 couples to Gas, adenylyl cyclase and cAMP production. To follow specific populations of OSN axons, GPR12 transgenic mice will be crossed with OR-tauLacZ mice, such as the M71-tauLacZ strain. This will allow visualization of the coalescence of OSN axons. Aim 2 will investigate changes in cAMP-mediated downstream signaling events that lead to alterations in gene expression. Identification of cAMP driven signal transduction in immature OSNs will help to elucidate mechanisms that control the position of OSN axon convergence in the olfactory bulb. Aim 3 will test whether cAMP over expression will rescue the lack of target innervation in mice lacking the emx2 gene. The results from these studies will provide novel insight into the role of cAMP signaling in OSN axon growth and convergence in the olfactory bulb. PUBLIC HEALTH RELEVANCE: Cell replacement as a regenerative approach to repair the injured nervous system remains promising. My research aims will contribute to understanding the processes that allow normal cellular replacement and appropriate target innervation in the olfactory system. This understanding of endogenous neural replacement can only help advance the design of effective regenerative therapies for brain and spinal cord injuries.